1,3-di-(4-piperidyl)propane derivatives



United States Patent 3,420,836 1,3-DI-(4-PIPERIDYL)PROPANE DERIVATIVESBernard Brust, Parsippany, Troy Hills, Rodney Ian Fryer, North Caldwell,and Leo Henryk Sternbach, Upper Montclair, NJ., assignors to Hotfmann-LaRoche Inc., Nutley, N.J., a corporation of New Jersey No Drawing.Continuation-impart of application Ser. No. 380,949, July 7, 1964. Thisapplication June 21, 1965, Ser. No. 465,774

U.S. Cl. 260-293 5 Claims Int. Cl. C07d 31/24; C07d 65/14; C07d 63/18ABSTRACT OF THE DISCLOSURE 1,3-di-(4-piperidyl)propane derivativeshaving an alkyl, cycloalkyl, phenyl, substituted phenyl or 5- or6-membered heterocyclic group in 2-position are prepared byhydrogenating the corresponding piperidyl derivatives. The products arepharmacologically useful as anti-depressants.

This application is a continuation-in-part of application Ser. No.380,949, filed July 7, 1964, now abandoned.

This invention relates in general to novel compounds and -to processesfor the production thereof. More particularly, the invention relates topharmacologically active piperidyl compounds and to processes forproducing same.

The compounds of this invention, broadly, are selected from the groupconsisting of members having the formula Br I in which R is a memberselected from the group consisting of hydrogen, an alkyl group havingfrom 1 to 12 carbon atoms, a cycloalkyl group having from 3 to 8 carbonatoms, an aryl radical, an aralkyl radical, a S-member saturatedheterocyclic radical and a -6-member saturated heterocyclic radical; inwhich R is a member selected from the group consisting of hydrogen andhydroxy; in which R is a member selected from the group consisting ofhydrogen and an alkyl group having from 1 to 6 carbon atoms; and inwhich R, is a member selected from the group consisting of hydrogen andan alkyl group having from 1 to 6 carbon atoms and salts thereof withmedicinally acceptable acids.

The term alky which appears in the immediately preceding paragraph, andwhich, in various instances, will appear in the paragraphs followinghereinafter, includes both straight and branched chain radicals, whichare substituted or unsubstituted. Moreover, the terms aryl and aralkyland the expression 5- and 6-member saturated heterocyclic radicals,which are used in the preceding paragraph, and which will be used insubsequent paragraphs, include substituted as well as unsubstitutedradicals. The expression medicinally acceptable acids which will be usedthroughout the specification and in the claims embraces inorganic acids,such as, hydrochloric acid, nitric acid, etc., as well as organic acids,such as, maleic acid and p-toluene sulfonic acid.

One group of compounds which are produced in the practice of thisinvention are those having the formula in which the symbol R is a memberselected from the group consisting of hydrogen, an alkyl group havingfrom 1 to 12 carbon atoms, a phenyl radical, a halogen-substitutedphenyl radical, a lower alkyl-substituted phenyl 3,420,836 Patented Jan.7, 1969 in which R is hydrogen, an alkyl group having from 1 to 12carbon atoms, a phenyl radical, a lower alkyl-substituted phenylradical, a halogen-substituted phenyl radical or a cyclohexyl radical;and in which the symbols R and R have the same meanings as in Formulas Iand II and salts thereof with medicinally acceptable acids.

A second group of compounds falling within the scope of Formula I arethose having the formula maiDom--om-O-m in which the symbols R R and Rhave the same significance as in Formula I and acid addition saltsthereof.

Additionlly, the invention embraces compounds having the formula inwhich the symbols R R and R have the same significance as in Formula I.The compounds of Formula II(b) are obtained by the dehydration of theFormula II(a) compounds.

As used in this specification, the expression lower alkyl denotes analkyl group having from 1 to 6 carbon atoms. The expression halogenincludes chlorine, bromine, fluorine and iodine.

The alkyl groups, which in the foregoing Formulas I, I I, II(a) andII(b) and III are represented by the symbol R includes, for example,methyl, ethyl, propyl, butyl, isopropyl, pentyl, hexyl, heptyl, etc.,radicals as well as such radicals substituted with a cycloalkyl radical,for example, a cyclohexyl radical. The cycloalkyl groups, which inFormulas I, II, II(a) and II(b) as represented by the symbol R include,for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl radicals. Specific examples of the arylradials which are represented in Formulas I, II, II(a), II(b) and/or IIIby the symbol R are a phenyl radical; lower alkyl-substituted phenylradicals, such as, methylphenyl, ethylphenyl, propylphenyl, butylphenyl,etc. radicals; halogensubstituted phenyl radicals, such as,fluorophenyl, bromophenyl, etc.; lower alkoxy-substituted phenylradicals, such as, methoxyphenyl, ethoxyphenyl, etc., radicals; loweralkylmercaptophenyl radicals, such as, methylmer- 'capto-phenyl,ethylmercapto-phenyl, etc. radicals. Benzyl is an example of an aralkylradical which, in Formulas I, II, II(a) and II(b), is represented by thesymbol R Specific examples of the 5- and 6-member saturated heterocyclicradicals, which in Formulas I, II(a) and II(b) are represented by thesymbol R include, pyrrolidinyl, tetrahydrofuryl, tetrahydrothienyl,piperidyl, tetrahydropyranyl, tetrahydrothiopyranyl,etc. radicals, aswell as, lower alkyl-substituted derivatives, for example, methyl,ethyl, propyl, etc., thereof.

The compounds of Formulas I, II and III are readily produced by any oneof several processes. In a first such process a compound having theformula OH IV in which R is an alkyl group having from 1 to 12 carbonatoms, an alkenyl group having from 2 to 12 carbon atoms, an alkynylgroup having from 2 to 12 carbon atoms, a cycloalkyl group having from 2to 8 carbon atoms, an aryl radical, an aralkyl radical, a S-memberheterocyclic radical and a 6-member heterocyclic radical or a hydrogenatom is reacted with hydrogen using a suitable hydrogenation catalyst inthe presence of an acid. As the catalyst system there can be used, forexample, platinum in hydrochloric acid. In effecting this reaction, theamount of hydrogen used will be dependent upon the degree ofunsaturation in the starting material. For example, in this method notonly will the terminal pyridyl groups be converted into piperidylgroups, but also alkenyl and alkynyl groups and unsaturated 5- and6-member heterocyclic radicals, if any of such groups or radicals are,in fact, present, will be converted into the respective saturatedcounterparts. The hydrogenation is carried out, ordinarily, at atemperature elevated above about room temperature and under pressure.Preferably, the catalytic hydrogenation reaction is carried out at thetemperature within the range of about 45 to 75 C. under a hydrogenpressure of from about 40 to about 80 atmospheres.

In a second preparative method for the compounds of Formulas I, II andIII the compound of Formula IV is reacted with a dehydrating agent toobtain a compound having the formula in which the symbol R has the samemeaning as in Formula IV. Dehydration of the Formula IV compound toobtain the desired intermediate Formula V compound is effected,conveniently, by heating the Formula IV compound, preferably at atemperature within the range of from about 60 to about 100 C., with aconcentrated mineral acid, such as, sulfuric acid, hydrochloric acid,nitric acid, etc. If desired, however, the dehydration reaction can becarried out using, as the dehydrating agent, a phosphorous trihalide,such as, phosphorous trichloride, phosphorous tribromide; aceticanhydride; or a mixture of acetic anhydride and zinc chloride. Moreover,the dehydration can be carried out by refluxing the Formula IV compoundin a solution of iodine in, for example, benzene, xylene, toluene, etc.

In a next step in this second preparative method, the Formula V compoundis converted into a propane compound having the formula wherein R hasthe same meaning as in any of Formulas I, II or III by hydrogenation. Inthis step, the hydrogenation is effected by catalytic means using, forexample, palladium, platinum, Raney nickel, etc., as the catalyst.Temperatures and pressures will be variable depending upon the compoundto be hydrogenated and the catalyst used. Subsequently, the terminalpyridyl radicals of the Formula VI compound are converted, byhydrogenation into piperidyl radicals to thus yield the compound ofFormula I, II or III wherein R and R are hydrogen. Hydrogenation of thepyridyl groups is carried out, catalytically, using platinum inhydrochloric acid or rhodium in ethanol.

In an alternate embodiment, the propene compound of Formula V is reactedwith hydrogen, in the presence of platinum in hydrochloric acid orrhodium in ethanol as a catalyst, to yield, directly, the desiredcompound of Formula I, II or III. With respect to the latter reaction,it has been found that, where platinum in hydrochloric acid is used asthe catalyst, a mixture is obtained when the compound in use contains aphenyl group at the 2-position, i.e., where the compound to behydrogenated is a Formula V compound in which R is phenyl. Such mixturecontains predominately the compound of Formulas I, II or III in which Ris a phenyl radical. However, there is present also in the reactionmixture, a compound of Formula I, II or III in which R is a cyclohexylgroup.

The N-alkyl-substituted compounds of Formulas I, II and III can beobtained by any conventional alkylation procedures from thecorresponding unsubstituted compound. Thus, for example, the compoundsof Formulas I, II or III in which R, and R are methyl groups can beprepared by reacting the compounds of Formulas I, II or III wherein Rand R are hydrogen atoms, with a mixture of formic acid andformaldehyde.

In another alternative preparative method, an alcohol of Formula IV isquaternized by any conventional means, for example, using an alkylhalide, to yield a compound having the formula wherein the symbol Xrepresents halogen and wherein the symbols R and R are alkyl groupshaving from 1 to 6 carbon atoms and R has the same meaning as in FormulaIV. The quaternary compound of Formula VII, While dissolved in asuitable solvent, is subsequently reduced with hydrogen in the presence,for example, of platinum oxide and potassium acetate to yield a compoundhaving the formula VIII in which the symbols R and R are alkyl groupshaving from 1 to 6 carbon atoms and R has the same meaning as in FormulaI. The compound of Formula VIII can be obtained also by the alkylationof the corresponding compound in which the symbols R and R representhydrogen atoms. Thereafter, the compound of Formula VIII is dehydratedin the same manner described previously for the dehydration of thecompound of Formula V to yield a compound having the formula wherein thesymbols R and R each represent alkyl groups having from 1 to 6 carbonatoms and in which R has the same meaning as in Formula IV. Compounds ofFormula V and IX are mixtures of stereoisomers and these isomers can beseparated, if desired, by conventional methods. Upon hydrogenation ofthe compound of Formula IX, while dissolved in water and glacial aceticacid in the presence of platinum, there is obtained a compound ofFormula I in which R represents an alkyl group having from 1 to 6 carbonatoms; R represents an alkyl group having from 1 to 6 carbon atoms; andR represents hydrogen.

In still another preparative method, the compounds of Formula I, inwhich R is hydrogen, R is hydrogen and R is hydrogen, are prepared bythe following sequence of reactions:

formula l R -N OHz-C H-CH2- N which, in turn, can be converted into acompound of the formula The compound of Formula (g) can, if desired, beconverted into a compound of the formula in each of which formulas R hasthe same meaning as in Formula I and in each of which R and R representalkyl groups which formula, it Will be appreciated, corresponds toFormula I in which R and R are alkyl groups.

In a further embodiment of the invention, the compound of Formula (b)can be converted directly to the compound of Formula I in which R is ahydroxy group and in which R and R are hydrogen atoms. Morespecifically, the compounds of Formula (b) can be converted directlyinto compounds having the formula:

in which the symbol R has the same meaning as in Formula I.

The piperidyl compounds of Formula (a) are prepared by the catalyticreduction of the corresponding pyridyl compound. Thus, for example,4-phenacylpiperidine, a preferred starting material, is obtained byhydrogenating 4-phenacylpyridine, at elevated temperature and underpressure, in the presence of platinum catalyst.

In preparing the alcohols of Formula (b), the piperidyl compound ofFormula (a) is reacted with a pieolyl metal, preferably while dissolvedin a suitable solvent. The procedure which is used in preparing theFormula (b) compounds is analogous to that described hereinafter for thepreparation of the Formula TV alcohols.

The propenes of Formula (c) are obtained by the dehydration of theFormula (b) alcohols. In general, the dehydration procedure isconventional. It is carried out in a manner analogous to that, describedheretofore, for the production of the propenes of Formula V. Preferably,the dehydration is effected by refluxing the alcohol of Formula (b) witha suitable mineral acid, such as, hydrochloric acid.

The propanes of Formula (d) are prepared by the catalytic hydrogenationof the propenes of Formula (c). In general, the hydrogenation procedureused will be analogous to that described heretofore for the conversionof the propenes of Formula V into the propanes of Formula VI.Preferably, however, the propene is hydrogenated, in ethanol, in thepresence of a palladium on carbon catalyst.

The propanes of Formula ((1) are converted to the propanes of Formula(e) by hydrogenation, in ethanol, in the presence of rhodium catalyst.

The direct conversion of the Formula (b) compound to the Formula Icompound, in which R is hydroxy and in which R and R are hydrogen atoms,is readily accomplished. Such conversion can be accomplished byhydrogenating the Formula (b) compound, while dissolved in dilutehydrochloric acid, in the presence of platinum catalyst at atmosphericpressure and at a temperature of about 25 C. The use of other reactioncon ditions will, however, be readily apparent to persons skilled in theart.

The compounds of Formula (d) can be converted into the compounds ofFormula (f) by a conventional alkylation procedure. For example, thecompound of Formula (d) can be converted to the compound of Formula (f)in which R is methyl by reacting said compound, dissolved in formic acidwith formaldehyde. The compound, thus obtained, can be converted intothe correspondingly substituted compound of Formula (g) by hydrogenatingsaid compound, in the presence of platinum catalyst, at atmosphericpressure and at about room temperature. The compound of Formula (g) inwhich R is a methyl group can be alkylated to provide the compound ofFormula (h). For example, the compound of Formula (g) in which R is amethyl group can be converted to the compound of Formula (h) in which Ris a methyl group by reacting said Formula (g) compound, while dissolvedin formic acid with formaldehyde.

The starting alcohols of Formula IV are readily prepared. For thepurposes of illustration, alternate processes will be described hereinfor producing the starting alcohols. It should be fully understood,however, that neither the alcohols, nor the processes for producingsame, are part of this invention. In general, the alcohols of Formula IVare conveniently prepared by reacting a 4-picolyl metal compound havingthe formula (I) HzM in which the symbol M represents an alkali metal,such as, sodium, potassium or lithium either with an acid halide havingthe formula R COHa1 XI in which the symbol R has the same meaning as inFormula IV and in which Hal represents a halogen atom or with an esterhaving the formula R COOX XII in which the symbol R has the same meaningas in Formula IV and in which the symbol X represents an alkyl, phenylor benzyl radical. More specifically, the alcohols of Formula IV areprepared by reacting a 4- picolyl metal compound of Formula X with anacid halide of Formula XI, such as, benzoyl chloride; ahalogen-substituted benzoyl chloride, for example, 3-fiuorobenzoylchloride, 4-fluorobenzoyl chloride, 4-chlorobenzoyl chloride etc.; alower alkyl-substituted benzoyl chloride, for example, p-toluoylchloride; a lower alkoxy-substituted benzoyl chloride, for example,methoxybenzoyl chloride; 9. lower alkylmercapto-substituted benzoylchloride, for example, methylmercaptobenzoyl chloride; acetyl chloride;isobutyryl chloride; octanoyl chloride; lO-undecenoyl chloride;phenacetyl chloride; a cycloalkyl carboxylic acid halide, for example,cyclopropyl carboxylic acid chloride, cyclobutyl carboxylic acidchloride, cyclopentyl carboxylic acid chloride, cyclohexyl carboxylicacid chloride; cycloheptyl carboxylic acid chloride, cyclooctylcarboxylic acid chloride; a halide of a 5- or 6-member heterocycliccarboxylic acid, for example, a halide of a pyridine carboxylic acid,such as, a chloride of 2-pyridine carboxylic acid, a chloride of4-pyridine carboxylic acid; a halide of a furoic acid, such as, achloride of 2- furoic acid; a halide of a thiophene carboxylic acid,such as, a chloride of 2-thiophene carboxylic acid; a halide of a pyrrolcarboxylic acid, such as, a chloride of 2-pyrrol carboxylic acid; or ahalide of a lower alkyl-substituted derivative of such 5- or 6-m'embercarboxylic acids. Obviously, halides of the named compounds, other thanchlorides can be used.

In the alternate process for producing the starting materials of FormulaIV, the 4-picolyl metal compound of Formula X is reacted with an esterof Formula XII, such as an alkyl ester of benzoic acid, for example,methyl benzoate, ethyl benzoate, etc.; an alkyl ester of analkylsubstituted benzoic acid, for example, the methyl ester of toluicacid, the ethyl ester of toluic acid; an alkyl ester of ahalogen-substituted benzoic acid, for example, methyl chlorobenzoate,ethyl chlorobenzoate, methyl fluorobenzoate, ethyl fiuorobenzoate, etc.;benzylbenzoate; a benzyl ester of an alkyl-substituted benzoic acid, forexample, the benzyl ester of toluic acid; a benzyl ester of ahalogenated benzoic acid, for example, benzyl chlorobenzoate, benzylfluorobenzoate; an alkyl ester of a lower alkoxy-substituted benzoicacid, for example, the methyl ester of methoxy-substituted benzoic acid;an alkyl ester of an alkylmercapto-substituted benzoic acid, forexample, the methyl ester of methylmercapto benzoic acid; a benzyl esterof an alkoxy-substituted benzoic acid, for example, the benzyl ester ofmethoxy-substituted benzoic acid; a benzyl ester of a loweralkylmercapto-substituted benzoic acid, for example, the benzyl ester ofmethylmercapto benzoic acid; an alkyl ester, such as, a methyl, ethyl,propyl, butyl, etc. ester, of, for example, acetic acid isobutynic acid,octanoic acid, IO-undecenoic acid or a benzyl or phenyl ester of such anacid; an alkyl ester of a cycloalkyl carboxylic acid, for example, themethyl, ethyl, butyl, etc. esters of cyclopropyl carboxylic acid,cyclobutyl carboxylic acid, cyclopentyl carboxylic acid, cyclohexylcarboxylic acid or a phenyl or benzyl ester of such cycloalkylcarboxylic acid; an alkyl ester, for example, a methyl, ethyl, propyl,butyl, etc. ester of 5- or 6-member heterocyclic acid, such as,2-pyridine carboxylic acid, 4-pyridine carboxylic acid, Z-furoic acid,2-thiophene carboxylic acid, or a phenyl or benzyl ester of such aheterocyclic carboxylic acid.

The reaction of the 4-picolyl metal compound of Formula X with eitherthe Formula XI compound or the Formula XII compound to produce theFormula IV starting material is carried out preferably in an inert S01-vent, for example, benzene, diethyl ether, toluene, 4-picoline,tetrahydrofuran, at a temperature within the range of from about l0 C.to about 60 C. In carrying out such reaction, there is used, preferably,a ratio of at least about 2.0 moles of the 4-pico1yl metal compound ofFormula X for each mole of the Formula XI or XII compound employed.Obviously, however, a larger or smaller quantity of the 4-picolyl metalcompound can be used in the reaction, if desired. The reaction productof Formula IV, the starting material used herein, can be isolated fromthe reaction mixture and, if desired, purified by any conventionalprocedure.

The compounds of this invention exhibit useful and entirely unexpectedpharmacological activity. For example, in varying degrees, the compoundsantagonize tetrabenazine ptosis in mice; potentiate DOPA, i.e.,dihydroxy phenylalanine, excitation in mice; potentiate amphetamineexcitation in behavior studies in rats; potentiate cocaine excitation inrats; potentiate low doses of tetrabenazine excitation in rats andpotentiate norepinephrine pressor effects in dogs. The compounds are,accordingly, useful as antidepressants.

The manner in which the present compounds are used as medicaments willbe readily apparent to persons skilled in the art. In general, thepharmacologically active compounds are formulated, together withconventional inert adjuvants, either inorganic or organic in nature,into dosage form suitable for oral or parenteral administration. Suchadjuvants include, for example, water, gelatin, lactose, starch,magnesium stearate, talc, vegetable oils, gums, polyalkylene glycols,etc. Moreover, the products can be sterilized and/or mixed with, forexample, preservatives, stabilizers, wetting or emulsifying agents,salts for altering osmotic pressure, buffers, etc. The dosage forms intowhich the present compounds can be formulated include tablets, capsules,suspensions, solutions, etc. The frequency of administration of thevarious dosage forms is variable depending to a large extent on the typeof dosage form, and the potency thereof, in use and on the needs andrequirements of the patient.

For a fuller understanding of the nature and objects of this invention,reference may be had to the following examples which are given merely asfurther illustrations of the invention and are not to be construed in alimiting sense.

Example 1 (A) In this example, 50 grams (172.3 millimoles) ofZ-phenyl-l,3-di(4-pyridyl)-2-propanol was dissolved in 600 ml. of 3 Nhydrochloric acid. This solution was reacted with hydrogen, :at atemperature of 55 to 60 C. under 60 atmospheres of pressure, in thepresence of 5 grams of platinum as the hydrogenation catalyst. When thehydrogenation was completed, a clear colorless solution was obtained.This solution was filtered to remove therefrom the platinum catalyst,following which the filtrate was cooled with 1 kg. of ice and madestrongly alkaline using 10 N sodium hydroxide solution. An oil wasdeposited by the last step and this oil was extracted four times, using200 ml. of methylene chloride each time. The methylene chloride extractswere combined and, thereafter, washed with water, two times, using ml.of water each time. Subsequently, the methylene chloride extracts werewashed again, two times, using 100 ml. of brine each time. The washedextracts were then dried over anhydrous sodium sulfate and concentratedin vacuo to an oil.

A substantial portion of the oily residue, which was obtained in theconcentration step, was dissolved in ml. of isopropyl alcohol and 70 ml.of a solution of hydrogen chloride in isopropyl alcohol was addedthereto. The resulting solution was cooled in an ice 'bath to form acrystalline product. The crystalline product was separated byfiltration, washed with 100 ml. of a mixture of isopropanol-ether (1:1)and dried. The product, namely, 2-

9 phenyl-l,3-di(4 piperidyl)propane dihydrochloride hydrate was obtainedin the form of colorless needles melting at 170 to 175 C.

The remainder of the oily residue obtained upon extraction of thereaction mixture with methylene chloride and its subsequentconcentration in vacuo was distilled at 176 C./0.5 mm. Upon cooling, thedistillate crystallized. The crystals, thus obtained, wererecrystallized from hexane to yield the pure base, that is,2-phenyl-1,3-di(4- piperidyl)propane as colorless prisms melting at 69-72 C.

To 4 grams (0.014 mole) of Z-phenyl-1,3-di(4-piperidyl)propane, therewas added 90 ml. of isopropanol and 2.9 grams (0.029 mole) ofconcentrated sulfuric acid. After 30 minutes, the solution was filteredand the 2- phenyl-l,3-di(4-piperidyl)propane disulfate salt wasrecrystallized twice from a methanol-ether mixture (1:1) to givecolorless prisms melting at 222-235 C.

To 4 grams (0.014 mole) of 2-pheny'l-l,3-di(4-piperidyl)propane, therewas added 100 ml. of methanol and 3.4 grams (0.029 mole) of 85%phosphoric acid. After stirring for one hour, 50 ml. of ether was added.The 2- phenyl-1,3-di(4-piperidyl)propane diphosphate salt was obtainedby filtration and it was recrystallized twice from a mixture of 15 ml.of warm water and 15 ml. of ethanol to give colorless rods melting at2l7231 C.

To a solution of 5.0 grams (17.44 millimoles) of 2-phenyl-1,3-di(4-piperidyl)propane in 15 ml. of ethanol, there was addeda hot solution of 6.06 grams (52.2 millimoles) of maleic acid in 15 ml.of ethanol. Upon the slow addition of 200 ml. of ethyl ether, the2-phenyl-l,3di(4- piperidyDpropane dimaleate salt precipitated ascolorless prisms, M.P. 160-171 C.

(B) A mixture of 5.0 grams (0.0174 mole) of 1,3-di(4-piperidyl)2-phenylpropane, produced as described in section A hereof,4.5 grams (0.088 mole) of 90% formic acid and 1.1 gram (0.0387 mole) of37.5% formaldehyde was refluxed for a period of fifteen hours. At theend of that time 5 ml. of hydrochloric acid was added, following whichthe mixture was evaporated almost to dryness under reduced pressure. Thesolution was made alkaline using N sodium hydroxide and, thereafter,extracted two times using 50 ml. of ether each time. The ether extractswere combined, washed with 40 ml. of saturated brine, dried overanhydrous sodium sulfate and taken down to dryness.

The colorless oil which was thus obtained was crystallized from ether toyield 1,3-bis(1-methyl-4-piperidyl)-2- phenylpropane in the form ofwhite rods melting at a temperature of 96 to 97 C.

For the sake of completeness, the preparation of theZ-phenyl-1,3-di(4-pyridyl)-2-propanol starting material is set forthhereinafter although it should be understood that neither the compounditself nor the process for its preparation comprises a part of theinstant invention.

An ether-benzene solution of 1.89 liters containing 3.5 moles of phenyllithium was added, over a 3 hour period, to a stirring solution of 326grams of 4-picoline (3.5 moles) in 800 ml. of tetrahydrofuran. Thisaddition was carried out in an atmosphere of dry nitrogen. When theaddition of the phenyl lithium solution to the 4-picoline solution wascompleted, the reaction mixture was stirred for an additional minutes.The reaction mixture was then cooled to a temperature of about C. Therewas thus produced picolyl lithium.

A mixture of 197 grams of benzoyl chloride (1.4 mole) and 100 ml. oftetra-hydrofuran was added to the picolyl lithium solution, produced asdescribed in the preceding paragraph, over a fifty-minute period. Duringthis addition, the temperature of the reaction mixture was maintained atabout 20 C. A pale green colored reaction mixture was obtained and itwas stirred at a temperature of about 20 C. for a period of about sixtyminutes. Thereafter, the reaction mixture was brought to about roomtemperature, at which temperature the mixture was stirred for a periodof about sixty minutes. Subsequently,

ml. of water was added to the reaction mixture a dropwise manner. Thereaction mixture was then diluted with 1 liter of water, stirredvigorously and transferred to a separatory funnel. In this vessel, thereaction mixture was acidified using 800 ml. of 6 N hydrochloric acid.The acid layer was separated from the organic phase and the latter wasextracted two times, using 200 ml. of 3 N hydrochloric acid each time.The acid extracts were combined, washed first three times using 500 ml.of toluene each time, and, subsequently, one time using 500 ml. ofether. Subsequently, 5 kg. of ice was added to the acid extracts whichwere then made alkaline using ammonium hydroxide. During this step, theacid extracts were maintained at a temperature of about 10 C.

Treatment of the acid extracts with alkali, as described in thepreceding paragraph, resulted in the formation of a precipitate. Thisprecipitate was recovered by filtration, following which it was washedfive times using 1.0 liter of water each time. The precipitate was thenpartitioned between 400 ml. of methylene chloride and 600 ml. of waterand the mixture was thoroughly shaken. The insoluble residue was removedby filtration and washed two times using 200 ml. of water each time.Thereafter, the residue was washed two times using 200 ml. of methylenechloride each time and one time using 200 ml. of ether. The product wasthen dried in a vacuum oven at a temperature of 50 C. (20" Hg) for aperiod of about 15 hours. There was obtained by this procedure,2-phenyl-1,3-di(4-pyridyl)-2-propanol melting first at 92 to 99 C.,resolidifying and melting again at 166 to 168 C.

Example 2 This example is included herein to show an alternatepreparative method for 2-phenyl-1,3-di(4-piperidyl)propanedihydrochloride monohydrate and to demonstrate a procedure for obtaining2-cyclohexyl-1,3-di(4-piperidyl) propane.

In this example, 100 grams (0.344 mole) of 2-phenyl-1,3-di(4-pyridyl)2-propanol, produced as described in Example 1, wasdissolved in 500 ml. of 75 percent sulfuric acid. This solution washeated at a temperature of 100 C. for a period of about 2 hours. At theend of that period of time, the reaction mixture was cooled in an icebath for about 10 minutes, following which it was poured into a mixtureof ice and ammonium hydroxide. An oil was deposited in the latter stepand this oil was extracted from the alkaline aqueous phase, five times,using 500 ml. of ether each time. The combined ether extracts weresubsequently washed three times using 100 ml. of water each time and twotimes using 100 ml. of brine each time. Thereafter the washed etherextracts were dried over anhydrous sodium sulfate and concentrated invacuo to an oil. There was thus obtained a mixture of the cis and transisomers of 1,3-di(4-pyridyl)-2- phenyl-l-propene. This mixture wassubsequently dissolved in 1 liter of 3 N hydrochloric acid andhydrogenated at a temperature of from about 50 to 55 C., under 60atmospheres of pressure, in the presence of 5.0 grams of platinum as thehydrogenation catalyst. After the required amount of hydrogen had beenabsorbed, the catalyst was removed by filtration to yield a clearcolorless solution. This solution was poured into a mixture of 600 ml.of 10 N sodium hydroxide and 1 kg. of ice and the mixture was extracted,five times, using 500 ml. of ether each time. The ether extracts werecombined, washed, three times, using 200 ml. of water each time and onetime using 100 ml. of brine. The washed ether extracts were subsequentlydried over anhydrous sodium sulfate, filtered and concentrated in vacuoto an oil which crystallized upon standing.

The crystalline product, which thus obtained, compris ing essentially2-phenyl-1,3-di(4-piperidy1)propane, was

dissolved in 500 ml. of isopropyl alcohol. Thereafter, 128 ml. of asolution of hydrogen chloride in isopropyl alcohol was added to thatsolution. Subsequently, 1 liter of ether was added to the mixture,following which the mixture was cooled in an ice bath. The product, thusformed, was recovered from the mother liquor by filtration andrecrystallized from a mixture of 500 ml. of methanol and 1 liter ofether to yield 2-phenyl-1,3-di(4-piperidyl)propane dihydrochlon'demonohydrate melting at 170 to 175 C.

The mother liquor from the preceding step was concentrated andcrystallized from a methanol-ether mixture to give2-cyclohexyl-1,3-di(4-piperidyl)propane, in the form of itsdihydrochloride salt, melting at 240 to 250 C. with decomposition. Thesalt was dissolved in water and the solution made alkaline with sodiumcarbonate. The aqueous solution was extracted with methylene chloride,following which the extracts were dried and evaporated to dryness. Thisresidue, crystallized from hexane, yielded2-cyclohexyl-1,3-di(4-piperidyl)propane in the form of colorless prisms,melting at 78 to 80 C.

Example 3 This example is included herein to demonstrate an additionalmethod for preparing 2-phenyl-1,3-di(4 piperidyl)propane.

In this example, 5.3 grams (19.3 millimole) of 2-phenyl-l,3-di(4-pyridyl) propane was dissolved in 200 ml. of ethanol.This solution was treated with 100 atmospheres of hydrogen at atemperature of 96 C. in the presence of about 1.0 gram rhodium as thehydrogenation catalyst. The bomb was washed with ethanol, followingwhich the catalyst was removed by filtration. Concentration of thefiltrate in vacuo yielded 5.40 grams of a colorless oil which, onstanding, formed a crystalline mass. This crystal-line mass,recrystallized from hexane, yielded 2-phenyl- 1,3-di(4-piperidyl)propanein the form of colorless needles melting at 70 to 72 C. Upon treatmentof this compound with dry hydrogen chloride in isopropyl alcohol, therewas obtained the corresponding dihydrochloride hydrate salt, in the formof colorless needles, melting at 170 to 175 C. with decomposition.

For the sake of completeness, the preparation of 2-phenyl-1,3-di(4-pyridyl)propane starting material is set forthhereinafter although it should be undertsood that neither the compounditself nor the process for its preparation comprises part of thisinvention. A solution of 10.0 grams (37 millimoles) of a 1:1 mixture ofcis 1,3-di(4- pyridyl)-2-phenyl-l-propene and trans 1,3-di(4-pyridyl)-2-phenyl-1-propene in 250 ml. of ethyl acetate was first prepared. Theisomeric mixture used was prepared as described in Example 2. To thissolution there was added 1.0 gram of percent palladium on charcoal. Theproduct was, thereafter, hydrogenated at a temperature of about 25 C. atatmospheric pressure. Over a period of about 72 hours, one molarequivalent of hydrogen was absorbed. At the end of that period of time,the catalyst was removed by filtration, following which the filtrate wasconcentrated in vacuo to yield Z-phenyl-1,3-di(4-pyridyl)- propane, inthe form of crystals, melting at -45 to 60 C. Recrystallization of thecompound from ether-hexane yielded the product in the form of colorlessprisms melting at 53 to 60 C.

Example 4 In this example, there was first prepared a solution of 5.0grams (17 millimoles) of 2-cyclohexyl-1,3-di(4- pyridyl)-2-propanol in70 ml. of a 75 percent by volume solution of concentrated sulfuric acidin water. This solution was stirred for a period of about 45 minutes ata temperature of about 100 C. At the end of that period of time, thereaction mixture was poured into a mixture of ice and concentratedammonium hydroxide. The alkaline solution was thereafter extracted threetimes with ether, dried over magnesium sulfate and filtered throughalumina (Woelm, neutral, activity grade 1). Removal of the solvent, invacuo, yielded 2-cyclohexyl-1,3-di(4- pyridyl)propene as a colorlessoil. This oil was dissolved, thereafter, in 200 ml. of ethanol andtreated with 100 atmospheres of hydro-gen at a temperature of 92 C. inthe presence of 1.0 gram of rhodium as a hydrogenation catalyst. Whenthe hydrogenation was completed, the catalyst was removed by filtration.The filtrate was, subsequently, concentrated in vacuo to yield2-cyclohexyl- 1,3-di(4-piperidyl)propane as a mass of colorless waxyplates melting at 74 to C.

For the sake of completeness, the preparation of the 2-cyclohe'xyl-1,3-di(4-pyridyl)2-propanol starting material is set forthhereinafter although it should be understood that neither the compounditself nor the process for its preparation comprises part of thisinvention.

A solution of 23.9 grams (0.2 mole) of hexahydrobenzoyl chloride in 75ml. of anhydrous tetrahydrofuran was added slowly over a period of about30 minutes to a solution of 0.5 mole of 4-picolyl lithium in 200 ml. oftetrahydrofuran. During such addition, the latter solution wasmaintained at a temperature of about 20 C. When the addition wascompleted, the reaction mixture was stirred at a temperature of 20 C.for a period of about thirty minutes, following which it was stirred atroom temperature for a period of about two hours. At the end of thatperiod of time, 1.0 liter of water was added to the reaction mixture.The resulting solution was acidified using 3 N hydrochloric acid. Atwo-layer system was formed. These layers were separated and the organicbase was extracted two times using 200 ml. of hydrochloric acid eachtime. The acid extracts were combined, washed three times using 200 ml.of ether each time, and made alkaline with 10.0 N sodium hydroxidesolution. The alkaline solution was allowed to stand at room temperatureovernight and as a result thereof a precipitate formed. The precipitatewas removed by filtration, washed, first, five times using ml. of watereach time, and thereafter, three times using 100 ml. of ether each time.The precipitate was recrystallized from an acetone-hexane mixture toyield 2-cyclohexyl-1,3-di(4-pyridyl)-2-propanol, as colorless prismmelting at 176 to 178 C.

Example 5 In this example, a solution of 13.4 grams (46.2 millimoles) ofa mixture of the cis and trans isomers of 2-(2-fiuorophenyl)-1,3-di(4-pyridyl)1-propene in 200 ml. of ethanol wastreated with hydrogen at 100 atmospheres of pressure and at atemperature of 100 C. in the presence of 1.0 gram of rhodium. The bombwas washed with ethanol and the catalyst was removed :by filtration. Thereaction mixture was concentrated in vacuo to yield a colorless oilwhich crystallized slowly to yield2-(o-fiuorophenyl)-1,3-di(4-piperidyl)propane in the form of waxy prismsmelting at 62 to 725 C. Treatment of this product with dry hydrogenchloride in isopropyl alcohol yielded 2- o-fiuorophenyl) 1,3 di(4-piperidyl) propane dihydrochloride hemihydrate melting at 164 to 168C. with decomposition. Recrystallization of this product from anisopropyl alcohol-hexane mixture gave the pure hydrated salt, in theform of colorless needles, melting at 169 C. to 171 C. withdecomposition.

For the sake of completeness, the preparation of the2-(2-fluorophenyl)-1,3-di(4-pyridyl) 1 propene starting material is setforth hereinafter although it should be understood that neither thecompound itself nor the process for its preparation comprises part ofthis invention.

A solution of 9.5 grams (30.8 millimoles) of 2-(2-fiuorophenyl)-1,3-di(4-pyridyl)2-propanol in 75 ml. of sulfuric acid(75%) was first prepared. This solution was stirred for a period of fourhours at a temperature of about 85 C. Thereafter, the cooled reactionmixture was poured into 400 ml. of concentrated ammonium hydroxide and 1kg. of ice. The mixture was then extracted with ml. of ether, followingwhich the extracts were concentrated in vacuo. There was, thus obtained,an oily mixture of the cis and trans2-(Z-fluorophenyl)-l,3-di(4-pyridyl)- l-propene. Crystallization fromhexane yielded cis 2-(2- fluorophenyl)-1,3-di(4-pyridyl)1-propene in theform of colorless needles melting at 105 to 107 C. Concentration of thehexane mother liquor yielded the trans 2-(fluorophenyl)-1,3-di(4-pyridyl)1-propene in the form of light yellowprisms melting at 88 to 90 C.

The 2 (2 fluorophenyl)-1,3-di(4-pyridyl)2-pr0panol starting material wasprepared by reacting 4-picolyl lithium with Z-fluorobenzoyl chloride,the process being carried out in the same manner as described in Example1 for the production of 2-phenyl-1,3-di(4-pyridyl)2-propanol.

Example 6 In this example, 8.5 grams (0.0282 mole) of 2-methyl-1,3-di(4-pyridyl) propane dissolved in 150 ml. of 3 N hydrochloric acidwas reduced with hydrogen in the presence of 0.2 gram of platinum. Thehydrogenation was carried out at a pressure of 60 atmospheres and at atemperature within the range of from about 55 to 65 C. The reaction wascontinued until seven molar equivalents of hydrogen had been absorbed.When the reaction was completed, the reaction mixture was filtered toremove the platinum catalyst. Subsequently, the filtrate was madestrongly alkaline using N sodium hydroxide solution and extracted threetimes using 100 ml. of methylene chloride each time. The methylenechloride extracts were collected and combined following which theextracts were washed three times using 25 ml. of water each time, driedover anhydrous sodium sulfate, filtered and concentrated. There wasobtained in the form of an oil, 2-methyl-1,3- di(4-piperidyl)propane.This base was dissolved in a small amount of isopropanol and thesolution was saturated with hydrogen chloride. The reaction mixture wasfiltered and the solid product thus obtained recrystallized fromisopropanol to give 2-methyl-1,3-di(4-piperidyl)propane dihydrochloridein the form of white prisms melting at 291 to 298 C. with decomposition.

For the sake of completeness, the preparation of the2-methyl-1,3-di(4-pyridyl)propane starting material is set forthhereinafter although it should be understood that neither the compounditself nor the process for its preparation comprises a part of theinstant invention.

A solution of 0.5 mole of 4-picolyl lithium in tetrahydrofuran was firstprepared. This solution was brought to a temperature within the range offrom about 30 to 50 C. To this cooled solution there was added, under anatmosphere of dry nitrogen, 0.2 mole of acetyl chloride dissolved in 150ml. of tetrahydrofuran. This addition was effected in a dropwise fashionover a period of about sixty minutes. Thereafter, the reaction mixturewas stirred overnight, following which it was diluted with 100 ml. ofwater. The reaction mixture was then extracted three times using 150 ml.of 6 N hydrochloric acid each time. The acid extracts were then stirredinto a mixture of 500 grams of ice and 300 ml. of concentrated ammoniumhydroxide with the temperature being maintained at about 0 C.

The clear solution, obtained as described in the preceding paragraph,was thereafter extracted three times using 150 ml. of methylene chlorideeach time. The organic extracts were combined, dried over magnesiumsulfate and reduced, in vacuo, to an oil. Trituration with hexaneyielded 2-me'thyl-1,3-di(4-pyridyl)2-propanol as yellow crystals meltingat 120 to 125 C. Recrystallization of the product three times from anacetone-hexane mixture yielded the compound, in the form of colorlessblocks, melting at 127 to 128 C.

A solution of 10.0 grams (0.0437 mole) of 2-methyl-1,3-di(4-pyridyl)2-propanol in 50 ml. of sulfuric acid (70%) wasprepared and stirred for a period of twentytwo hours at a temperature ofabout 75 C. The solution, at the end of that period of time, was cooledin an icebath, made alkaline with ammonium hydroxide and extracted twotimes, using 100 ml. of methylene dichloride each time. The organiclayers were then combined, washed with 75 ml. of saturated brine, driedover sodium sulfate and concentrated. The residual oil containing2-methyl- 1,3-di(4-pyridyl)1-propene was dissolved in benzene andchromatographed on 70 grams of alumina (neutral grade 1). It was elutedwith 200 ml. of benzene, 200 ml. of methylene dichloride and 200 ml. ofmethanol.

Fractions 1 and 2 were combined and dissolved in 50 ml. of methanol. Thesolution was, thereafter, saturated.

with hydrogen chloride, following which 100 ml. of ether was addedthereto. The salt which precipitated from solution was recovered byfiltration. Recrystallization of the precipitate from a methanol-ethermixture containing a trace of water yieldedZ-methyl-1,3-di(4-pyridyl)-1- propene dihydrochloride hydrate in theform of white rods, melting at 181 to 186 C.

A solution of 15 .0 grams (71.5 millirnoles) of 2-methyl-1,3-di(4-pyridyl)1-propene, produced as described in the precedingparagraphs was dissolved in 300 ml. of ethyl acetate. To this solutionthere was added 1.0 gram of 10% palladium on carbon catalyst. Thecompound was, thereafter, hydrogenated at atmospheric pressure and roomtemperature. The reaction mixture absorbed the required amount ofhydrogen, i.e., one molar equivalent in a period of about six hours. Atthe end of that period, the catalyst was separated from the reactionmixture by filtration, following which the filtrate was concentrated toan oil under reduced pressure. The residue was then dissolved in 200 ml.of anhydrous ether and saturated with hydrogen chloride. Theprecipitated oil crystallized upon the addition of a small amount ofmethanol. Recrystallization of the product from a methanol-ether mixtureyielded 2-methyl-1,3-di(4-pyridyl)propane dihydrochloride as colorlessprisms melting at 223 to 245 C.

Example 7 In this example, 5.0 grams (17.3 millimoles) of 1,3-di(4-pyridyl)-2-(p-tolyl)propane dissolved in 200 ml. of ethanol wasreduced with hydrogen at 100 atmospheres of pressure and at atemperature of C. in the presence of 1.0 gram of rhodium. When thereaction was completed, the bomb was washed with ethanol and the rhodiumcatalyst was removed by filtration. Thereafter the solvent was removedfrom the filtrate in vacuo to yield1,3-di(4-piperidyl)-2-(p-tolyl)propane in the form of colorless crystalsmelting at 104-107 C. Recrystallization of the compound from hexaneyielded the pure product in the form of colorless prisms melting at 106to 108 C.

For the sake of completeness, the preparation of the 1,3-di(4-pyridyl)-2-(p-tolyl)propane starting material is set forthhereinatfer although it should be understood that neither the compounditself nor the process for its preparation comprises part of thisinvention.

A solution of 5.0 grams (16.5 millimoles) of 1,3-di(4-pridyl)-2-(p-tolyl)-2-propanol in 50 ml. of sulfuric acid (75 percent)was first prepared. This solution was stirred at a temperature of 75 C.for a period of about eighteen hours. At the end of that period of timethe reaction mixture was poured into 250 ml. of concentrated ammoniumhydroxide and 500 grams of ice. The mixture was, thereafter, extractedwith 150 ml. of ether, following which the ether extracts were driedover magnesium sulfate and concentrated in vacuo. There was, thusobtained, a mixture of the cis and trans isomers of 1,3-di(4-pyridyl)-2-(p-tolyl)-l-propene in the form of an oil. On standing,this oil solidified, melting point at to 118 C. Recrystallization of thesolid product from hexane yielded the pure cis1,3-di(4-pyridyl)-2-(p-tolyl)- l-propene, melting at 116 to 117.5 C.

In this example, a solution of 1.3 grams (4.54 millimoles) of cis1,3-di(4-pyridyl)-2-(p-tolyl)-1-propene, produced as described in thepreceding paragraph in 200 ml. of ethyl acetate was first prepared. Tothis solution there was added 250 mg. of 10 percent palladium on carbonas a catalyst. The product was then hydrogenated at room temperature andatmospheric pressure. Over a period of about four hours, one molarequivalent of hydrogen was absorbed. Thereafter, the catalyst wasremoved by filtration and the solvent was removed, under reducedpressure, to give 1.3 grams of oil. Recrystallization from hexane-etheryielded 1,3-di(4-pyridyl)-2-(p-tolyl)- propane melting at 94 to 96 C.

The starting 1,3di(4-pyridyl)-2-(p-tolyl)-2-propanol was prepared by thereaction of p-toluoyl chloride with 4-picolyl lithium, the said processbeing carried out in the same manner as described in Example 1 for theproduction of Z-phenyl- 1, 3-di(4-pyridyl -2-propanol.

Example 8 In this example, 20 grams of Z-phenyl-1,3-di(4-pyridyl)2-propanol, produced as described in Example 1, was treated with anexcess of methyl iodine and allowed to stand at room temperature for aperiod of eighteen hours. The reaction mixture was thereafter filteredand the product, thus obtained, recrystallized from isopropanol to yield2-phenyl-1,3-di(4-pyridyl)-2propanol dimethiodide, melting at 189 to 191C.

The quaternary compound (30 grams), which was prepared as described inthe preceding paragraph, was dissolved in 200 ml. of ethanol andhydrogenated for a period of about eight hours at 35 atmospheres ofpressure and room temperature in the presence of 1.0 gram of platinumoxide and 10.0 grams of potassium acetate. The catalyst was then removedby filtration and the filtrate was concentrated under reduced pressure.The residue was, thereafter, partitioned between 150 ml. of ether and 15ml. of water. The aqueous layer was made basic with ammonium hydroxideand extracted three times, using 100 ml. of ether each time. The etherlayers were combined, washed three times, using 100 ml. of water eachtime, dried over anhydrous sodium sulfate, filtered and evaporated.Crystallization and recrystallization of the residue from cyclohexanegave 1,3-bis(1-methyl-4-piperidyl)-2-phenyl-2-propanol, melting at 119to 121 C.

A solution of 8.1 grams (0.0247 mole) of 1,3-bis(1-methyl-4-piperidyl)-2-phenyl-2-propanol in 100 ml. of concentratedhydrochloric acid was refluxed for a period of fifteen hours. At the endof that period of time, the reaction mixture was cooled in an ice bath,made alkaline with 10 N sodium hydroxide and extracted two times using100 ml. of ether each time. The organic layers were combined, washedwith 75 ml. of saturated brine solution and dried over anhydrous sodiumsulfate. Subsequently, the solution was evaporated to dryness. Theresidue was dissolved in 40 ml. of petroleum ether and chromatographedon 100 grams of basic alumina. The column was eluted with 100 ml. ofbenzene and 250 ml. of ether. The two fractions were combined andevaporated to dryness. There was obtained1,3-bis(1-methyl-4-piperidyl)-2-phenylpropene in the form of a colorlessoil. This base was dissolved in ethanol and cooled to a temperature of 5C. Hydrogen chloride gas was then bubbled into the solution.Recrystallization of the salt which precipitated from an ethanol ethermixture yielded 1,3-bis(1-methyl-4-piperidyl)-2-phenylpropenedihydrochloride hydrate, as white needles, which melted at 270 C. to 275C.

A solution of 0.1 gram (0.00323 mole) of 1,3-'bis(1-methyl-4piperidyl)-2-phenylpropene in 20 ml. of glacial acetic acid and20 ml. of water was hydrogenated at room temperature and atmosphericpressure in the presence of 50 mg. of platinum. After the absorption ofone molar equivalent of hydrogen, the solution was filtered throughCelite, washed with water and made alkaline with N sodium hydroxide. Thesolution was then extracted three times, using 40 ml. of ether eachtime. The organic layers were combined, washed with saturated brinesolution, dried over anhydrous sodium sulfate and evaporate-d todryness. Recrystallization of the residue from ether gave1,3-bis(l-methyl-4-piperidyl)-2-phenylpropane, in the form of white rodsmelting at 96 to 97 C.

Example 9 In this example, a mixture of 25.0 grams (86 millimole) ofZ-phenyl-l,3-di(4 pyridyl)-2!propanol, produced as described in Example1, 1.0 gram of rhodium metal catalyst and 200 ml. of ethanol was treatedwith hydrogen at a temperature of C. under 100 atmospheres of pressure.When the hydrogenation was completed, the catalyst was removed byfiltration, following which the solvent was removed under reducedpressure. There was, thus obtained, a colorless oil which, on standing,solidified to a crystalline mass, melting at 64 to 72 C. This mass wasrefluxed in hexane giving 2-phenyl-1,3-di(4-piperidyl)-2- propanol, inthe form of colorless prisms melting at 123 to 126 C.

Example 10 A solution of 19.7 grams (0.10 mole) of 4-phenacylpyridine ina mixture of 200 ml. of ethanol and 9 ml. of concentrated hydrochloricacid was hydrogenated in the presence of 1.0 gram of platinum catalystunder 500 lbs. of pressure at 30 C. After the required amount ofhydrogen had been absorbed, the catalyst was separated by filtration.The filtrate was then concentrated, in vacuo, to give4-phenacylpiperidine hydrochloride which was recrystallized frommethanol, as colorless prisms, M.P. 245 to 249 C. TheA-phenacylpiperidine free base was subsequently obtained by dissolvingthe salt in water, making the solution alkaline with dilute sodiumhydroxide, extracting the free base, thus formed into dichromomethane,washing the dichloromethane layer with water, drying same over anhydroussodium sulfate and concentrating same to an oil.

To a stirred solution of 0.88 mole of gamma picoline in 300 m1.tetrahydrofuran (purified by filtering over Woelm neutral alumina),under dry nitrogen, a solution of 0.88 mole of phenyl lithium in about350 ml. of benzene and ether was added dropwise over a period of onehour. The reaction mixture was held at a temperature of 15 C. to 25 C.during the addition and was then stirred for a period of about thirtyminutes at room temperature. The stirred solution was cooled to atemperature within the range of from about 20 to 30 C. and a solution of4-phenacylpiperidine (0.352 mole) in 200 ml. of tetrahydrofuran wasadded dropwise over a twenty-five minute period. The reaction mixturewas stirred at 20 to -25 C. fo one hour, subsequently at roomtemperature for thirty minutes, following which it was hydrolyzed with50 ml. of water. The reaction mixture was poured into 2 liters of waterand acidified to pH 1 with concentrated hydrochloric acid. The acidlayer was separated and the organic layer was further extracted with 200ml. of 3 N hydrochloric acid. The acid extracts were combined, washedfour times, using 300 ml. of ether each time, and made very stronglybasic with 10 N sodium hydroxide solution. The resulting precipitate wasseparated by filtration and washed thoroughly with water.Recrystallization from an acetoneether mixture gave2-phenyl-1-(4-piperidyl)-3-(4-pyridy1)- 2-propanol as colorless rodsmelting at 128 C.

A solution of 7.1 grams (24.9 millimole) of the2-phenyl-1-(4-piperidyl)-3-(4-pyridyl)-2-propanol in 50 m1. ofisopropanol was treated with 40 ml. of a 5.5 N solution of hydrogenchloride in isopropanol. The base was produced as described in thepreceding paragraphs. The salt which was thus formed was precipitated asan oil with 200 ml. of ether and the supernatant solution was decanted.The residue was crystallized from a methanol-ether mixture to give2-phenyl-1-(4-piperidyl)- 3-(4-pyridyl)-2-propanol dihydrochloridemonohydrate as colorless prisms melting at 168l78 C., withdecomposition.

1 7 Example 11 A. A solution of 90 grams (0.34 mole) of 2-phenyl-1-(4-piperidyl)-3-(4-pyridyl)-2-propanol produced as described inExample 10, and 1.0 liter of 9 N hydrochloric acid was refluxed forseventeen hours and poured into a mixture of 1.2 liters of 10 N sodiumhydroxide solution and 500 grams of ice. The deposited oil was extractedwith a 1:1 ether-benzene mixture, five times using 500 ml. of theether-benzene mixture each time. The combined extracts were washed fourtimes using 200 ml. of water each time, dried over anhydrous sodiumsulfate, filtered, and concentrated in vacuo. The residue was dissolvedin ethanol and one equivalent of a solution of maleic acid in ethanolwas added. The salt which crystallized was removed by filtration andrecrystallized from ethanol to give the purecis-2-phenyl-3-(4-piperidyl)-l-(4-pyridyl)- l-propene maleate in theform of white prisms melting at 172l78 C., with decomposition.Cis-Z-phenyl- 3-(4-piperidyl)-1(4-pyridyl)-1-propene, as the free base,was obtained by dissolving the maleate salt in water, making thesolution alkaline with dilute sodium hydroxide, extracting the freebase, thus formed, into dichloromethane, washing the dichloromethanelayer with water, drying same over anhydrous sodium sulfate andconcentrating the solution.

B. A solution of 8.0 grams (21.65 millimole) of2-phenyl-1-(4-piperidyl)-3-(4-pyridyl)-2-propanol dihydrochloridemonohydrate, produced as described in Example 10, in 150 ml. of waterwas hydrogenated in the presence of a platinum catalyst at atmosphericpressure and at a temperature of 25 C. After the required amount ofhydrogen had been absorbed, the catalyst was separated by filtrationover a small pad of Hyflo. The filtrate was cooled with 100 grams of iceand made strongly alkaline with a 10 N sodium hydroxide solution. Thedeposited oil crystallized upon standing overnight and wasrecrystallized from hexane to give the product1,3-di(4-piperidyl)-2-phenyl2-propanol as colorless rods melting at120-124 C.

Example 12 A solution of 2-phenyl-3-(4-piperidyl)-1-(4-pyridyl)-l-propene (55.5 millimole), produced as described in Example 11, in 200ml. of ethanol was hydrogenated at a temperature of 45 to 50 C. under apressure of 33.3 atmospheres in the presence of 5 grams of percentpalladium on carbon. After the required amount of hydrogen was absorbed,the catalyst was filtered and the filtrate was concentrated in vacuo.The residue was dissolved in ml. of isopropanol and one equivalent of a5.5 N solution of isopropanolic hydrogen chloride was added. Thesolution was cooled and the product crystallized by the slow addition ofether. Recrystallization from an isopropanol-ether mixture gave2-phenyl- 1-(4-piperidyl)-3(4pyridyl)propane hydrochloride as colorlessprisms melting at 196207 C., with decom' position. The free base, i.e.,2-phenyl-1-(4-piperidyl)-3- (4-pyridyl)propane was obtained bydissolving the hydro chloride salt in water, making the solutionalkaline with dilute sodium hydroxide, extracting the free base, thusformed, into dichloromethane, washing the dichloromethane layer withwater, drying the washed extracts over anhydrous sodium sulfate andconcentrating the extracts.

Example 13 A. A solution of Z-phenyl-l-(4-piperidyl)-3(4-pyridyl)propanehydrochlorine (15.75 millimoles), produced as described in Example 12,in ml. of ethanol was hydrogenated at a temperature of 8090 C. under apressure of 100 atmospheres in the presence of 1.0 gram of rhodium.After the required amount of hydrogen was absorbed, the catalyst wasremoved by filtration and 5 ml. of a 5.5 N solution of isopropanolichydrogen chloride was added to the filtrate. The solution was cooled inan ice :bath and the product precipitated by the addition of 200 ml. ofhexane to give 2-phenyl-l,3-di(4-piperidyl) propane dihydrochloridemonohydrate as colorless needles melting at 170-175 C., withdecomposition.

B. A solution of 9.3 grams (33.2 millimoles) of 2-phenyl-l-(4-piperidyl)-3-(4-pyridyl)propane, produced as described inExample 12, in 25 ml. of percent formic acid was cooled in an ice bathand 10 ml. of 37.5 percent formaldehyde was added. The reaction mixturewas heated under reflux for 17 hours on a steam bath, 6 ml. ofconcentrated hydrochloric acid was added and the reaction mixtureconcentrated in vacuo to an oil. The residue was dissolved in 25 ml. ofwater and the solution was made strongly basic by the addition of 10 Nsodium hydroxide. The deposited oil was extracted into three times,using ml. of ether each time, washed twice using 50 ml. of water eachtime, then washed with 50 ml. of brine, dried over anhydrous sodiumsulfate and concentrated in vacuo to an oil. The oil was dissolved in 25ml. of methanol, cooled in an ice bath and 1 ml. of concentratedsulfuric acid was added. 1-(1-rnethyl-4-piperidyl)- 2-phenyl 3(4-pyridyl)propane disulfate crystallized, upon the slow addition ofether, as colorless prisms melting at 2l0222 C. Thereafter, the freebase, that is, 1-( l-methyl-4-piperidyl)-2-phenyl-3- (4 pyridyl)propane, was obtained by dissolving the disulfate salt in water, makingthe solution alkaline with dilute sodium hydroxide, extracting the freebase, thus formed, into dichloromethane, washing the dichloromethanelayer with water, drying the washed extracts over anhydrous sodiumsulfate and concentrating the extracts.

Example 14 A solution of 4.9 grams (16.7 millimoles) of l-(1-methyl-4-piperidyl) -2-phenyl-3- (4-pyridyl) propane, produced asdescribed in Example 13, in 200 ml. of 1 N HCl was hydrogenated in thepresence of a platinum catalyst at atmospheric pressure and at atemperature of 25 C. After the required amount of hydrogen had beenabsorbed, the catalyst was separated by filtration over a small bed ofHyflo. The filtrate was cooled with 100 grams of ice and made stronglyalkaline with a 10 N sodium hydroxide solution. The deposited oil wasextracted three times using 100 ml. of an ether-benzene mixture (1:1)each time. The combined extracts were washed three times using 50 ml. ofbrine each time, dried over anhydrous sodium sulfate and concentrated invacuo to a colorless oil. The oil, that is, crude 1-(1-methyl-4-piperidyl)-2-phenyl 3 (4 piperidyl)propane, was dissolved in 25 ml. ofethanol, cooled in an ice bath and one equivalent of para-toluenesulfonic acid was added. l-(l-methyl-4-piperidyl)-2-phenyl 3(4-piperidyl)propane para-toluene sulfonate crystallized upon the slowaddition of ether, as colorless prisms, melting at 153- 156 C.

Example 15 A solution of 2.7 grams (9.0 millimoles) of the crude1-(l-methyl-4-piperidyl)-2-phenyl 3 (4-piperidyl)propane produced asdescribed in Example 14, in 25 ml. of 90% formic acid was cooled in anice bath and 10 ml. of 37.5% formaldehyde was added. The reactionmixture was heated under reflux for 21 hours on a steam bath, 2 ml. ofconcentrated hydrochloric acid was added and the reaction mixtureconcentrated in vacuo to an oil. The residue was dissolved in 25 ml. ofwater and the solution was made strongly basic by the addition of 10 Nsodium hydroxide. The deposited oil was extracted three times intoether, using 100 ml. of ether each time, washed twice using 50 ml. ofwater each time and one time using 50 ml. of brine, dried over anhydroussodium sulfate and concentrated on a steam bath to a small volume. Uponcooling the ether solution in an ice .bath, the product, 1,3 di(1-methyl-4-piperi dyl)-2-phenylpropane, crystallized as colorless rods, meltingat 96 to 97 C.

Example 16 A soution of 1.5 grams (4.9 millimoles) of tris(4-pyridylmethyl)methanol in 35 ml. of ethanol was hydrogenated at 100 C.and 1500 p.s.i. under hydrogen in the presence of 0.25 gram of rhodiummetal catalyst. The bomb was washed with ethanol and the catalystremoved by filtration giving a colorless solution. Removal of thesolvent in vacuo gave tris(4-piperidylmethyl)methanol melting at 170 to177 C. Recrystallization from methylene chloride-hexane yielded thebase, in the form of colorless prisms, melting at 175 to 179 C.

Tris(4-pyridylmethyl)methanol, melting point of 205 to 206, was preparedby the dropwise addition of 0.2 mole of ethyl chloroformate, in drytetrahydrofuran to about 0.5 mole of 4-picolyl lithium at 40 C. Thereaction mixture, after hydrolysis with hydrochloric acid was worked upby conventional means to obtain the desired compound.

Example 17 A solution of 12.3 grams (38.4 millimoles) of 2-(4-methoxyphenyl)-1,3-di(4-pyridyl)2-propanol in 300 ml. of 3 Nhydrochloric acid was treated with hydrogen at 60 C. under 60atmospheres of pressure in the presence of 1.0 gram of platinumcatalyst. When the hydrogenation was completed, the reaction mixture wasfiltered to remove the catalyst and poured into an excess of icedammonium hydroxide. Extraction with methylene chloride followed bydrying over magnesium sulfate and removal of the solvent in vacuoyielded 2-(4-methoxyphenyl)-1,3- di(4-piperidyl)propane, as a paleyellow oil. Treatment of the free base, thus obtained, with an. excessof maleic acid in ethanol gave the dimaleate salt of 2-(4-methoxyphenyl)1,3 di(piperidyl)propane, melting at 170 to 174 C. An analytical samplewas prepared from ethanol as colorless prisms, melting at 170 to 174 C.

The 2-(4-methoxyphenyl) 1,3 di(4-pyridyl)-2-propanol, which was used asthe starting material in this example, was prepared by reacting 0.5 moleof 4-picolyl lithium with 0.2 mole of p-methoxy benzoyl chloride intetrahydrofuran as a solvent.

Example 18 In this example, a mixture of 4.95 grams (23 millimoles) of1,3-di(4-pyridyl)2-propanol in 100 ml. of ethanol was heated at atemperature of 100 C., under 100 atmospheres of hydrogen, in thepresence of 1.0 gram of rhodium metal catalyst. When the hydrogenationwas complete, the catalyst was removed by filtration and the solventremoved in vacuo to yield 1,3-di(4-piperidyl)-2- propanol as a colorlessoil which slowly crystallized to a mass, melting point at 100 to 110 C.Recrystallization from methylene chloride-hexane yielded 1,3-di(4-piperidyl)-2-propanol as colorless needles, melting at 115 to 117 C.

The 1,3-di(4-pyridyl)2-propanol starting material was prepared as*follows: to 0.5 mole of 4-picolyl lithium, stirred at 50 C. andprotected with dry nitrogen, there was added, in a dropwise fashion overa period of thirty minutes 14.8 grams (0.20 mole) of ethyl formate in 50ml. of tetrahydrofuran. The temperature of the reaction was allowed toreach room temperature, following which it was stirred overnight. Thereaction mixture was hydrolyzed and then extracted with 6 N hydrochloricacid. Neutralization of the acid extract with iced ammonium hydroxideand extraction with methylene chloride yielded, after drying overmagnesium sulfate and concentration in vacuo,1,3-di(4-pyridyl)2-propanol. Crystallization from hexane yieldedl,3-di(4-pyridyl)2-propanol melting at 95 to 105 C.

Example 19 In this example, a solution of 11.5 grams (38.8 mmole) of2-cyclohexyl-1,3-di(4-pyridyl)2-propanol in 300 ml. of ethanol washydrogenated in the presence of 1 gram of rhodium. The hydrogenation wascarried out for a period of 4.5 hours at a temperature within the rangeof from about 98 C. to 102 C. under an initial hydrogen pressure of 1515p.s.i. at room temperature. When the hydrogenation was complete, thesolvent and the catalyst were removed to obtain an oil, which uponcrystallization from hexane, yielded 2-cyclohexyl-1,3-di(4-piperidyl)-2-propanol melting at 110 C. to 113 C. Recrystallization of this productfrom hexane yielded 2-cyclohexyl-1,3-di(4- piperidyl)-2-propanol in theform of colorless plates melting at 113 C. to 115 C.

The preparation of the starting 2-cyclohexyl-1,3-di(4pyridyl)-2-propanol is given hereinafter for the sake of completeness ofdisclosure. It is to be understood, however, that neither the startingcompound nor the method for its preparation is part of this invention.In the preparative method, a solution of 23.9 grams (0.2 mole) ofhexahydrobenzoyl chloride in 75 ml. of anhydrous tetrahydrofuran wasadded slowly, over a period of about 30 minutes, to a 0.5 molar solutionof 4-picolyl lithium. During the addition, the latter solution wasmaintained at a temperature of about 20 C. When the addition wascompleted, the reaction mixture was stirred at a temperature of 20 C.for a period of about thirty minutes, following which it was stirred atroom temperature for a period of about two hours. At the end of thatperiod of time, 1.0 liter of water was added to the reaction mixture.The resulting solution was acidified using 3 N hydrochloric acid. Atwo-layer system was formed. These layers were separated and the organicbase was extracted two times using 200 ml. of hydrochloric acid eachtime. The acid extracts were combined, washed three times using 200 ml.of ether each time and made alkaline with 10 N sodium hydroxidesolution. The alkaline solution was allowed to stand at room temperatureovernight and, as a result thereof, a precipitate formed. Theprecipitate was removed by filtration, washed, first, five times using100 ml. of water each time, and, thereafter, three times using 100 ml.of ether each time. The precipitate was recrystallized from anacetone-hexane mixture to yield2-cyclohexy1-1,3-di(4-pyridyl)-2-propanol, as colorless prisms, meltingat 176 C. to 178 C.

Example 20 In this example, a mixture of 2.0 grams (6.95 mmole) of1,3-di(4-pyridyl)-2-(o-tolyl)propane, 200 ml. of ethanol and 1.0 gram ofrhodium was hydrogenated over a two hour period at a temperature withinthe range of from about C. to C. under an initial hydrogen pressure of1550 p.s.i. When the hydrogenation was complete, the catalyst and thesolvent were removed to yield 1,3-di(4-piperidyl)2-(o-tolyl)propane as apale yellow oil. Upon treatment with hydrogen chloride, there wasobtained 1,3-di(4-piperidyl)2-(o-toly1)propane dihydrochloridehemihydrate melting at 151 C., with decomposition.

While not within the scope of the present invention, the preparation ofthe starting 1,3-di(4-pyridy1)-2-(otolyl)-2-propane is given herein forcompleteness of disclosure. In the preparative method, 0.2 mole ofo-toluic acid chloride dissolved in 150 ml. of tetrahy-drofuran wasadded, in a dropwise fashion over a period of about sixty minutes, to astirred solution of 0.5 mole of 4-picolyl lithium. The addition wascarried out in an atmosphere of dry nitrogen, with the 4-picolyl lithiumsolution being cooled to -30 C. to 50 C. The reaction mixture wastreated with ml. of water within a three hour period, following which itwas extracted three times, using ml. of 6 N hydrochloric acid each time.The acid extract was washed three times, using 150 ml. of ether eachtime. The product was liberated by stirring with a mixture of 500 gramsof ice and 300 ml. of concentrated ammonium hydroxide. Ice was added, asneeded, to maintain the temperature at about 0 C.

The mixture was then filtered to yield an orange-colored 21 solid. Thesolid was washed with a mixture of 200 ml. of methylene chloride and 400ml. of water. The solid was then crystallized 'from acetone to yield1,3-di(4- pyridyl)-2-(o-tolyl)-2-propanol, melting at 154 to 156 C. aswhite prisms.

A solution of 10.0 grams (33 mmole) of l,3-di(4-pyridyl)-2-(o-tolyl)-2-propanol, produced as described in the precedingparagraph, in 75 m1. of 75% sulphuric acid was heated at a temperatureof about 95 C. for a period of about two hours. This solution was cooledand, thereafter, it was poured over iced ammonium hydroxide andextracted with ether. The extract was dried and concentrated, in vacuo,to provide an oil-like residue. This residue was subsequentlyhydrogenated at room temperature and atmospheric pressure in ethylacetate using a palladium-charcoal catalyst. When the hydrogenation wascomplete, the catalyst was removed by filtration, and the solvent wasremoved by heating in vacuo.

There was, thus obtained, 1,3-di(4-pyridyl)-2-(o-tolyl) propane in theform of an oil, which yielded crystals, melting point 100 C. to 103 C.,on standing. Recrystallization of the product from hexane yieldedcolorless needles, melting point at 100 C. to 102 C.

Example 21 In this example, a mixture of 3.0 grams (12.6 mole) of2-isopropyl-1,3-di(4-pyridyl)propene, 200 ml. of ethanol and 1.0 gram ofrhodium was hydrogenated for a period of about 2.5 hours at atemperature within the range of from about 90 C. to 100 C. under aninitial hydrogen pressure of 1450 p.s.i. When the hydrogenation reactionwas complete, the solvent and the catalyst were removed to yield an oilyresidue which crystallized slowly to a mass melting at 75 C. to 80 C.Recrystallization of this mass from hexane yielded 2-isopropyl-1,3-di(4-piperidyl) propane in the form of colorless prisms melting at77 C. to 79 C. Treatment of that compound with hydrogen chloride yieldedthe dihydrochloride salt of 2-isopropyl-1,3-di(4-piperidyl)propane,melting point at 330 C. to 335 C.

In an alternate preparative method, 13 grams (50.7 mmole) of2-isopropyl-1,3-di(4-pyridyl)propene in 200 ml. of 3 N hydrochloric acidwas directly dehydrated and reduced, in the presence of platinum oxideat a temperature of 60 C. and under hydrogen pressure of 955 psi. toyield 2-isopropyl-1,3-di(4-piperidyl)propane. This base was converted tothe dihydrochloric acid salt by treatment with hydrogen chloride.

The preparation of the 2-isopropyl-l,3-di(4-pyridyl) propene which isused as the starting material in this example is set forth hereinafterfor completeness of disclosure. It should be understood, however, thatneither the compound, nor the process for its preparation, is part ofthe present invention. Thus, in this preparative method, a solution of0.5 mole of 4-picolyl lithium in tetrahydrofuran was first prepared.This solution was brought to a temperature within the range from about30 C. to 50 C. To this cooled solution there was added, under anatmosphere of dry nitrogen, 0.2 mole of isobutyryl chloride dissolved in150 ml. of tetrahydrofuran. This addition was affected, in a dropwisefashion over a period of about sixty minutes. Thereafter, the reactionmixture was stirred overnight, following which it was diluted with 150ml. of water. The reaction mixture was extracted three times, using 100ml. portions of 6 N hydrochloric acid each time. The acid extracts werethen stirred in a mixture of 500 grams of ice and 300 ml. ofconcentrated ammonium hydroxide with the temperature being maintained atabout C. The product, thus obtained, was extracted three times, using150 ml. of methylene chloride, each time. The organic extracts weredried over magnesium sulfate and reduced, in vacuo to yield an oil-likeproduct. This oil was crystallized from hexane to yield2-isopropyl-l,3-di(4 pyridyl)-2-propanol, in crystalline form, meltingat 135 to 155 C. Recrystallization of the compound three times fromacetone herein yielded 2-isopropyl-1,3-di(4-pyridyl)-2-propanol in theform of colorless prisms, melting at 155.5 to 157 C.

A mixture of 5 grams of 2-isopropyl-l,3-di(4-pyridyl)- 2-propanol,produced as described in the preceding paragraph, and ml. of 75% byvolume of sulfuric acid, was heated at a temperature of 75 C. for 17hours. The acidic solution was poured into an excess of ice ammonia andextracted with methylene chloride. The organic extract was dried overanhydrous magnesium sulfate and it was concentrated, in vacuo, to yield2-isopropyl-l,3-di(4-pyridyl)propene as a colorless oil.

Example 22 A solution of 20 grams of Z-phenyl-l,3-di(4-piperidyl)-2-propanol in 25 ml. of concentrated hydrochloric acid was heated underreflux for a period of about 24 hours. At the end of that time, thereaction mixture was concentrated, under reduced pressures, and the oilyresidue thus obtained was crystallized from a mixture of isopropanol andether. Recrystallization from an isopropanolether mixture yielded2-phenyl-l,3-di(4-piperidyl)propene dihydrochloride hydrate as whiteprisms melting at 171 to 191 C., with decomposition.

A solution of 1 gram of the salt, obtained as described in the precedingparagraph, was treated an excess of dilute sodium carbonate solution andthe free base was extracted into ether (3X 30 ml.). The ether extractswere combined, washed with water, dried over sodium sulfate, filteredand evaporated to give, after concentrationZ-phenyl-l,3-di(4-piperidyl)propene free base in the form of whiteprisms. Recrystallization from an etherpetroleum ether mixture yieldedthe pure compound melting at 103 to 105.

The starting compound in the example, i.e. 2-phenyl-1,3-di(4-piperidyl)-2 propanol, was produced as described in Example 9.

Example 23 This example is included herein to demonstrate thepreparation of dosage forms containing as the active ingredientrepresentative compounds of this invention.

(a) Capsule formulation.-10 mg. of cis-2-phenyl-3 (4-pi-peridyl)-1-(4-pyridyl)-l-propene maleate were mixed with mg. oflactose, U.S.P. and 30 mg. of corn starch, U.S.P. The mixture was thenblended by passing through a Fitzpatrick Comminuting Machine with a No.1A screen with knives forward. The blended powder was, thereafter,returned to the mixer and 5 mg. of talc was added thereto and blendedtherewith. The product was subsequently filled into hard shell gelatincapsules.

(b) Tablet formulation.5.l0 mg. of cis-2-phenyl-3 (4-piperidyl)-l-(4-pyridyl)-l-propene maleate were mixed with 84.40 mg. oflactose, U.S.P., 10.0 mg. of corn starch and 0.5 mg. of magnesiumstearate. The mixture was blended by passing through a FitzpatrickComminuting Machine, fitted with a No 1A screen with knives forward. Thepowder was then slugged on a tablet compressing machine, following whichthe slugs were comminuted using a No. 16 screen. The mixture wascompressed at a tablet weight of 100 mg. using tablet punches having adiameter of approximately inch.

(c) Parenteral formulation.5.0 mg. of cis-2-phenyl-3(4-piperidyl)-1-(4-pyridyl)-l-propene maleate were slurried in a smallamount of water. To the slurry there was added slowly maleic acid to pHof 3.0. Thereafter, 4.5 mg. of phenol (anhydrous) was added to thesolution. The solution was filtered and allowed to stand for twentyfourhours. Thereafter, the filtrate was filtered through a 02 Selas candle.The filtrate was then filled into ampuls under an atmosphere ofnitrogen, which were then sealed. The ampuls were sterilized for twentyminutes at a temperature of 250 F.

Example 24 This example is included herein to demonstrate thepreparation of dosage forms containing as the active in- 23 gredientanother representative compound of this invention.

(a) Capsule formulation.-25 mg. of 2phenyl-1,3- di(4-piperidyl)propanedihydrochloride hydrate were mixed with 150 mg. of lactose, U.S.P. and30 mg. of corn starch, U.S.P. The mixture was then blended by passingthrough a Fitzpatrick Comminuting Machine with a No. 1A screen withknives forward. The blended powder was, thereafter, returned to themixer and 5 mg. of talc was added thereto and blended therewith. Theproduct was subsequently filled into hard shell gelatin capsules.

(b) Tablet formulation-40.20 mg. of 2-phenyl-1,3- di(4-piperidyl)propane dihydrochloride hydrate were mixed with 79.30 mg. of lactose,U.S.P., 10.0 mg. of corn starch and 0.5 mg. of magnesium stearate. Themixture -was blended by passing through a Fitzpatrick ComminutingMachine, fitted with a No 1A screen with knives forward. The powder wasthen slugged on a tablet compressing machine, following which the slugswere comminuted using a No. 16 screen. The mixture was compressed at atablet Weight of 100 mg. using tablet punches having a diameter ofapproximately A1 inch.

(c) Parenteral formulation.5.0 mg. of 2-phenyl-l,3di(4-piperidyl)propane dihydrochloride hydrate were slurried in a smallamount of water. To the slurry there was added slowly maleic acid to pHof 3.0. Thereafter, 4.5 mg. of phenol (anhydrous) was added to thesolution. The solution was filtered and allowed to stand for twenty-fourhours. Thereafter, the filtrate was filtered through a 02 Selas candle.The filtrate was then filled into ampuls under an atmosphere ofnitrogen, which were then sealed. The ampuls were sterilized for twentyminutes at a temperature of 250 F.

What is claimed is:

1. A compound selected from the group consisting of a member of theformula in which R is a member selected from the group consisting of .analkyl group having from 3 to 7 carbon atoms, a cycloalkyl group havingfrom 3 to 8 carbon atoms, phenyl, phenyl substituted by lower alkyl,halogen, lower alkoxy or lower alkylmercapto; benzyl, pyrrolidinyl,tetrahydrofuryl, tetrahydrothienyl, piperidyl, tetrahydropyranyl,tetrahydrothiopyranyl, or lower alkyl substituted pyrrolidinyl,tetrahydrofuryl, tetrahydrothienyl, piperidyl, tet-rahydropyranyl,tetrahydrothiopyranyl; in which R is a member selected from the groupconsisting of hydrogen and an alkyl group having 1 to 6 carbon atoms;and in which R, is a member selected from the group consisting ofhydrogen and an alkyl group having 1 to 6 carbon atoms and salts thereofwith medicinally acceptable acids.

2. Z-phenyl-l,3-di(4-piperidyl)propane. 3. 1,3-bis(l-methyl-4-piperidyl)-2-phenylpropane. 4. 1 (1 methyl 4 piperidyl) 2phenyl 3 (4- piperidyDpropane.

5. Z-isopropyl-l,3-di(4-piperidyl) propane.

References Cited UNITED STATES PATENTS 1/1953 Goldberg et a1 2602938/1966 Gurien et al 260-296 JOHN D. RANDOLPH, Primary Examiner.

US. Cl. X.R.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.5,420,836 January 7, 1969 Bernard Brust et all It is certified thaterror appears in the above identified patent and that said LettersPatent are hereby corrected as shown below:

Column 14, line 51, "hereinatfer" should read hereinaf1 line 55,"pridyl" should read H pyridyl Column 16, 11' 33, "dichromomethane"should read dichloromethane Colun 17, line 68, "hydrochlorine" shouldread hydrochloride line 68, "millimoles" should read millimole Column18, line 5, "millimoles" should read millimole Column 19, line 34, after"di(" insert 4- Column 24, lines 1 to 4,

the formula should appear as shown below:

R3-N CH2 -CHCH2 Signed and sealed this 17th day of March 1970.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. WILLIAM E. SCHUYLER, JR Attesting OfficerCommissioner of Patents

